Treatment of disorders such as schizophrenia and Alzheimer""s disease and other chronic CNS conditions are problematic in that strict compliance is important and often requires the aid of a caretaker. Ways of increasing compliance which would aid the patient and caretakers and are greatly desirable. 
which include compounds where: 
X is
n is 3;
R1 is C6-C10-aryl, R2 is selected from the group consisting of H and C1-C6 alkyl; R3 is COR5, and R5 is C3-C6 cycloalkyl, the optical isomers; and the pharmaceutically acceptable salts thereof.
Said compounds are taught to be useful in the treatment of anxiety, depression, schizophrenia, cognitive deficits, nausea and vomiting, and in the treatment of prostate cancer.

wherein
R1=H or lower alkyl of 1-4 carbon atoms,
R2=H or lower alkyl or 1-4 carbon atoms;
R3 is I and p is 0 or 1, and their pharmaceutically acceptable acid addition salts, display an unexpectedly long duration of action in vivo, making them particularly useful as 5-HT1A antagonists in the treatment of chronic diseases resulting from the dysfunction of the serotonergic 5-HT1A system.
Preferred compounds are those of the general formula I where: R1=H or CH3 and R2=H or CH3; and pharmaceutically acceptable acid addition salts thereof. The most preferred compounds of general formula I are 1-Methyl-cyclohexanecarboxylic acid {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amide 
and the pharmaceutically acceptable acid addition salts thereof.
The compounds of formula I contain an asymmetric carbon atom and may exist in different stereoisomeric forms, e.g. as a racemate or as optically active forms. The present invention encompasses the pure stereoisomers as well as racemates of Formula I.
Compounds of Formula I are useful for the treatment of chronic diseases resulting from the dysfunction of the serotonergic 5-HT1A system. With half-lives measured by days rather than hours, compounds of the present invention may be admininstered less frequently and are expected to be particularly useful for the treatment of conditions where compliance is traditionally problematic. A therapeutically effective dose of compounds of Formula I may be provided to a patient as infrequently as once during a seven day period. Dosing may be no more than once during a ten day period in some embodiments of the invention, and as infrequently as once every fourteen days in still other embodiments of the invention.
Compounds of the present invention may be administered to a patient suffering from chronic central nervous system disorders related to or caused by dysfuntion of the serotonergic 5-HT1A system, such as schizophrenia and other psychotic disorders such as paranoia and mano-depressive illness.
Similarly, the treatment of cognitive disorders with compounds having very long lasting effects would be particularly useful. For instance, treatment of cognitive deficits associated with Alzheimer""s disease and other dementias with a compound requiring less frequent dosing would improve compliance with such patients. Thus, compounds of the present invention may be useful for the treatment of cognitive disorders associated with mild cognitive impairment (MCI), Alzheimer""s disease and other dementias including Lewy Body, vascular, and post stroke dementias. Cognitive dysfunction associated with surgical procedures, traumatic brain injury or stroke may also be treated in accordance with the present invention. Further, compounds of the present invention may be useful for the treatment of diseases in which cognitive dysfunction is a co-morbidity such as, for example, Parkinson""s disease, autism and attention deficit disorders.
Anxiety (generalized anxiety disorder, panic attacks and obsessive compulsive disorder) may similarly be treated with compounds of the present invention having long duration of action.
Another condition where compliance is problematic and where compounds of the present invention are expected to have particular value is the treatment of alcohol and drug withdrawal, including nicotine withdrawal.
In addition, conditions where symptoms are exhibited in a chronic manner would be particularly amenable to treatment with compounds of the present invention. For example, chronic pain, motor disorders such as Parkinson""s disease, and Tourette""s syndrome could be treated with compounds of the present invention.
Other conditions where treatment with compounds having long duration of action may be advantageous are autism, attention deficit disorder, hyperactivity disorders, stroke, treatment of eating disorders such as obesity, anorexia, and bulimia, sexual dysfunction, sleep disorders, social phobias, thermoregulatory disorders, endocrine disorders, urinary incontinence, vasospasm and prostate cancer.
Recent clinical trials employing drug mixtures (e.g., fluoxetine and pindolol) have demonstrated a more rapid onset of antidepressant efficacy for a treatment combining SSRI activity and 5-HT1Aantagonism (Blier and Bergeron, 1995; F. Artigas et. al., 1996; M. B. Tome et. al., 1997). The compounds of the invention are thus exceedingly interesting and useful for treating depressive illnesses by potentiating inhibitors of serotonin reuptake such as SSRIs and SNRIs, including, but not limited to fluoxetine, venlafaxine, duloxetine, sertraline, paroxetine, fluvoxamine, nefazodone, and mirtazapine. Potentiating, as used herein refers to providing increased availability of serotonin compared the usual increase observed with administration of an inhibitor of serotonin reuptake alone, optionally with a more rapid onset of action. Thus compounds of the present invention may be provided no more than once during a seven day period in combination with a second component which is an inhibitor of serotonin reuptake.
The long-lasting effects of the compounds of this invention also make them useful as biological tools to study the role and effects of functional 5-HT1A antagonism in vivo and in vitro. The application of the long-lasting in vitro and in vivo effects of the compounds of this invention includes the use of the compounds of this invention labeled with isotopes of the naturally occurring elements within the structures of the compounds, e.g. radioactive isotopes or isotopically enhanced. Uses include, but are not limited to, use of the labeled compounds as radioligands for binding studies, use of the labeled compounds as radioligands for in vitro and in vivo imaging a population of cells, and use of the labeled compounds for positron emission topography (PET) studies in mammals including, but not limited to mouse, cats, dogs, monkeys and humans. The compounds would also have tremendous value as biological agents that are able to induce long-term blockade of the 5-HT1A receptor after an acute administration. The consequences of this can be studied in cellular preparations and in young and adult animals. These studies may be multidisciplinary and can investigate many parameters associated with, but not limited to, physiology, biochemistry, behavior and anatomy. This would allow investigations to examine the functional role of the 5-HT1A receptor in the brain as a whole after systemic injections or in discrete brain regions after intracerebral injections. This would have tremendous advantage over molecular biological manipulations such as knockout or transgenic animals and antisense technologies which are more challenging from a technical standpoint and require more time to achieve.
The compounds of the present invention can be prepared by conventional chemical methods which are well known to those skilled in the art of chemistry using chemicals that are either commercially available or readily prepared following standard literature procedures. For example, the compounds may be prepared by the general methods disclosed in WO 99/65887. Such disclosed methods include acylating an amine of formula III (where R2 is defined above) with an acylating agent of formula IV, where R1 is defined above (Scheme 1). Examples of acylating derivatives include but are not limited to acid halides (e.g., acid chloride), anhydrides and activated esters and amides. 
The starting materials of general formula III may be provided by the general route disclosed in WO 99/65887 and specifically by the exemplified route described WO 99/65887.
Isotopes may be introduced into the structures of the compounds of the present invention using literature methods and standard chemical methods that are well known to those skilled in the art of chemistry. Isotopes for labeling the compounds of this invention include, but are not limited to, 2H, 3H, 11C, 13C, 14C, 125I and 131I. Preferably, compounds of the invention are labeled with 3H, 11C, or 14C. For example, a precursor of the compound may be reacted with isotope containing reagent such that the isotope is incorporated into the resulting molecule. For example, a phenolic precursor of a compound of the invention may be alkylated with a labeled alkylating agent such as [3H]methyl iodide or [11C]methyl iodide to provide compound containing a labeled methoxy-substituted phenyl group, using the methodology described by Pike et al. (Med. Chem. Res. (1995), 5: 208). The phenolic precursor VI can be obtained by demethylation of the amine of formula III to give intermediate V (Scheme 2). Acylation of compound V gives the phenolic intermediate VI, which can be treated with methyl iodide containing an isotope (2H, 3H, 11C, 13C, 14C) to yield the final labeled product II. 
Throughout the schemes, labels are denoted with a xe2x80x9c* xe2x80x9d.
Carbon labels (11C, 13C, 14C) may also be introduced into the carbonyl moiety of the structures of the present invention according to the general methodology described by Pike et al. by treating the Grignard derivative of an appropriate cyclohexyl halide with labeled carbon dioxide to form labeled formula IV, which can then be used to acylate intermediate III, as shown in Scheme 3. 
In a further example, an ethylenically unsaturated precursor may be catalytically hydrogenated with tritium to provide the 3H-labeled compound. Alternatively, compounds of the invention may be labeled with 125I or 131I such as by methods described by Engel et al., Naunyn-Schmiedeberg""s Arch Pharmacol, 325:328-336 (1984); and Engel, et al., Naunyn-Schmiedeberg""s Arch Pharmacol, 317:277-285 (1981).
The following examples are included for illustrative purposes only and are not intended to be considered as limiting to this disclosure in any way.
Intermediate 1
Potassium t-butoxide is added portionwise to a stirred solution of propanethiol in dry DMF under an argon atmosphere. After 0.5 h, a solution of {(1R)-1-cyclohexylmethyl-2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-amine in dry DMF is added and the mixture is heated at 100xc2x0 C. overnight. A further quantity of potassium t-butoxide and propanethiol is then added and the mixture heated at 100xc2x0 C. for another 24 h. The cooled mixture is partitioned between water and ethyl acetate. The combined organic layers are washed with brine, dried and concentrated on a rotary evaporator to yield the desired product, which is purified by chromatography on alumina.
Intermediate 2
A solution of 1-methylcyclohexanecarbonyl chloride, triethylamine and {(1R)-1-cyclohexylmethyl-2-[4-(2-hydroxyphenyl)-piperazin-1-yl]-ethyl}-amine is stirred at 0xc2x0 C. under a nitrogen atmosphere for 1 hour. The mixture is then concentrated on a rotary evaporator and partitioned between ethyl acetate and saturated aqueous NaHCO3. The combined organic layers are washed with brine, dried and concentrated on a rotary evaporator to yield the desired product, which is purified by chromatography on alumina.